ADAM33 expression in asthmatic airways and human embryonic lungs
ADAM33 expression in asthmatic airways and human embryonic lungs
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DOI：
10.1164/rccm.200409-1251oc
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发表时间：
2005-05-01
影响因子：
24.7
通讯作者：
Davies, DE
中科院分区：
文献类型：
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作者：
Haitchi, HM;Powell, RM;Davies, DE
基本原理：ADAM 33（一种去整合素和金属蛋白酶）的多态性变异与不同人群中的哮喘和支气管高反应性密切相关。目的和方法：为了研究ADAM 33在哮喘中的作用，我们采用逆转录-定量聚合酶链反应和免疫化学方法研究了其在正常、哮喘和胚胎气道中的表达。结果如下：在支气管活检和胚胎肺中检测到几种ADAM 33 mRNA剪接变体;然而，编码金属蛋白酶结构域的β亚型和变体是罕见的转录本。支气管活检的蛋白质印迹法证实存在多种亚型的ADAM 33，其分子量为22，37，55和65 kD。成人支气管活检的免疫组织化学和激光共聚焦显微镜显示，α-平滑肌肌动蛋白和ADAM 33免疫反应性主要共定位于平滑肌和粘膜下层的孤立细胞。与对照组相比，哮喘患者的ADAM 33 mRNA扩增产物或蛋白质无显著差异。在发育中的肺中，在支气管周围发现了ADAM 33;然而，免疫反应性比未分化间质中的α-平滑肌肌动蛋白分布更广泛;在Western印迹上，检测到另外的25-kD ADAM 33变体。结论：几种ADAM 33蛋白亚型存在于成人支气管平滑肌和人胚胎支气管及其周围间质中，强烈表明其在平滑肌发育和/或功能中的重要性，这可以解释其与支气管高反应性的遗传关联。ADAM 33在胚胎间充质细胞中的存在表明，它可能参与气道壁的“建模”，有助于哮喘的早期生命起源。
Rationale: Polymorphic variation in ADAM33 (A Disintegrin And Metalloprotease) is strongly associated with asthma and bronchial hyperresponsiveness in different populations. Objective and Methods: To study the role of ADAM33 in asthma, we investigated its expression in normal, asthmatic, and embryonic airways using reverse transcriptase-quantitative polymerase chain reaction and immunochemistry. Results: Several ADAM33 mRNA splice variants were detected in bronchial biopsies and embryonic lung; however, the beta-isoform and variants encoding the metalloprotease domain were rare transcripts. Western blotting of bronchial biopsies confirmed the presence of multiple isoforms of ADAM33, which had molecular weights of 22, 37, 55, and 65 kD. Immunohistochemistry and laser confocal microscopy of adult bronchial biopsies showed that a-smooth muscle actin and ADAM33 immunoreactivity were mostly colocalized to smooth muscle and isolated cells in the submucosa. There was no significant difference in ADAM33 mRNA amplicons or protein in subjects with asthma compared with control subjects. In developing lung, ADAM33 was found around bronchial tubes; however, immunoreactivity was more widely distributed than a-smooth muscle actin within undifferentiated mesenchyme; on Western blots, an additional 25-kD ADAM33 variant was detected. Conclusions: Several ADAM33 protein isoforms occur in adult bronchial smooth muscle and in human embryonic bronchi and surrounding mesenchyme, strongly suggesting its importance in smooth muscle development and/or function, which could explain its genetic association with bronchial hyperresponsiveness. The occurrence of ADAM33 in embryonic mesenchymal cells suggests that it may be involved in airway wall "modeling" that contributes to the early life origins of asthma.